Antibody-drug conjugates (ADCs) are designed to deliver cytotoxic agents into targeted cells, and they are typically developed as treatments for cancer. Due to the need for new cancer drugs, the development of ADCs is the focus of substantial efforts by the biopharmaceutical industry. Nearly 60 ADCs are currently in clinical studies, one ADC, inotuzumab ozogamicin, is undergoing regulatory review, and three ADCs have been granted approvals, although the first to be approved, gemtuzumab ozogamicin (Mylotarg®) was withdrawn from the market in 2010.

Two ADCs, brentuximab vedotin (Adcetris®) and ado-trastuzumab emtansine (Kadcyla®), are currently marketed in the United States (US) and European Union (EU), as well as other countries. These two ADCs are disparate in their composition, and are used as treatments for different indications. Brentuximab vedotin is composed of an anti-CD30 monoclonal antibody (mAb) conjugated to the tubulin inhibitor monomethyl auristatin E via a valine-citruline dipeptide linkage designed for conditional cleavage inside cells. In contrast, ado-trastuzimab emtansine comprises an anti-human epidermal growth factor receptor-2 (HER2) mAb coupled to the tubulin-disrupting maytansinoid DM1 drug via a non-reducible thioether linkage. Brentuximab vedotin was granted its first approval in 2011 for two indications: 1) classical Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplantation or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates; and 2) systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. The first approval for ado-trastuzumab emtansine was granted in 2013; the product is indicated for the treatment of HER2-positive metastatic breast cancer in patients who previously received trastuzumab and a taxane separately or in combination.

Of the nearly 60 ADCs in the clinic, only two (depatuxizumab mafodotin, vadastuximab talirane) are currently in late-stage (Phase 2/3 or 3) clinical studies, but two additional ADCs (sacituzumab govitecan, mirvetuximab soravtansine) may transition to Phase 3 soon. Depatuxizumab mafodotin (ABT-414) is composed of an anti-epidermal growth factor receptor (EGFR) mAb conjugated to the tubulin inhibitor monomethyl auristatin F via a stable maleimidocaproyl linker. The Phase 2b/3 Intellance 1 study (NCT02573324) of the ADC with concurrent chemoradiation and adjuvant temozolomide in adult patients with newly diagnosed glioblastoma multiforme (GBM) with EGFR amplification was initiated in late 2015. Depatuxizumab mafodotin has orphan drug designations for GBM in the US and glioma in the EU, and it was granted a US Rare Pediatric Disease Designation for pediatric EGFR-amplified diffuse intrinsic pontine glioma, a brainstem tumor that is highly aggressive and difficult to treat. Vadastuximab talirane (SGN-33A) is an anti-CD33 mAb with 2 engineered cysteine residues through which DNA cross-linking pyrrolobenzodiazepine dimer drug moieties are conjugated via a protease-cleavable valine-alanine dipeptide linker. The Phase 3 CASCADE clinical trial (NCT02785900) of vadastuximab talirine in combination with azacitidine (Vidaza) or decitabine (Dacogen) in older patients with newly diagnosed acute myeloid leukemia (AML) was initiated in May 2016. Results from a Phase 1 study indicated that the ADC in combination with hypomethylating agents was a well-tolerated regimen with a high remission rate in older patients with AML.

The transitions of sacituzumab govitecan (IMMU-132) and mirvetuximab soravtansine (IMGN853) to Phase 3 may occur by the end of 2016. The start of a Phase 3 study (NCT02574455) that will evaluate the safety and efficacy of sacituzumab govitecan in refractory/relapsed triple-negative breast cancer (TNBC) patients is scheduled for December 2016. This ADC has received US Breakthrough Therapy and Fast Track designations for the treatment of patients with TNBC. Sacituzumab govitecan comprises an anti-TROP-2 mAb conjugated via a pH-sensitive linker to SN-38, the active metabolite of the chemotherapeutic irinotecan, in a site-specific manner. Mirvetuximab soravtansine is being assessed as a single-agent therapy in the FORWARD I trial (NCT02631876) of the ADC versus investigator’s choice of chemotherapy in adults with folate receptor (FR)-α positive advanced epithelial ovarian cancer, primary peritoneal cancer or primary fallopian tube cancer, which is being changed from a Phase 2 to a Phase 3 trial. Mirvetuximab soravtansine is composed of an anti-FRα mAb linked to the tubulin-disrupting maytansinoid DM4 via a cleavable linker.

It should be noted that, despite the increased complexity of the molecules, ADCs are also the focus of companies developing biosimilar products. As discussed in previous Society posts, biosimilars of antibody-based drugs that have lost patent protection, including adalimumab (Humira®), rituximab (Rituxan®, Mabthera®), trastuzumab (Herceptin®) and etanercept (Enbrel®), are already approved or undergoing regulatory review in the US and EU, as well as other countries.

As of mid-2016, 53 unique antibody therapeutics were in Phase 3 studies. This is the same total number noted in the “Antibodies to watch in 2016” article, but the antibodies included in the totals are not all the same. The tables included in this mid-year update result from the addition of antibodies that started a first Phase 3 study in late 2015 to mid-2016, and deletion of antibodies that transitioned to regulatory review, reverted to an earlier clinical phase or had their development suspended or terminated. Compared to the totals included in the “Antibodies to watch in 2016” article, the number of antibodies in Phase 3 studies for cancer indications as of mid-2016 decreased slightly (from 17 to 15, respectively), while those for non-cancer indications increased slightly (from 36 to 38, respectively).

Antibodies for cancer represent only 28% of the current commercial Phase 3 pipeline, although they are ~55% of the overall clinical pipeline of therapeutic antibodies. The 15 antibody therapeutics in Phase 3 studies for cancer indications are notable for the diversity in their composition. Of the 15, 6 (40%) are non-canonical antibodies (1 radiolabeled antibody, 1 scFv-containing liposome, 2 immunotoxins, 2 antibody-drug conjugates (ADCs)), and a majority of the canonical antibodies (i.e., full-length IgG1, 2 or 4) are Fc- or glyco-engineered to enhance functionality. The 2 ADCs now in Phase 3 studies represent a vanguard, as this type of antibody therapeutic has entered clinical studies in large numbers only recently. Of the ADCs currently in clinical studies, most (44/56, 79%) are in either Phase 1 or Phase 1/2 studies, and most (55/56) are for cancer indications. ADCs now comprise ~20% of the clinical pipeline of antibodies for cancer, but ~11% of all antibodies in clinical development. There is substantial diversity of the targets, drugs, linkers, and drug-to-antibody ratios of the ADCs in the clinic. For example, of the ADCs in the clinic, targets for 51 have been disclosed, and 39 of these 51 targets are unique, i.e., only one ADC in clinical studies is known to target that particular antigen. Antigens known to be the target of more than one ADC in clinical studies include CD19, CD37, EGFR, HER2 and mesothelin. The diversity of the molecules may initially serve as a hindrance, but knowledge gained by the development of this class of molecules should increase overall as more ADCs enter clinical studies, transition through the phases and join the two ADCs currently on the market, brentuximab vedotin (Adcetris®) and ado-trastuzumab vedotin (Kadcyla®).

Antibodies for non-cancer indications dominate the current commercial Phase 3 pipeline. Unlike the antibodies for cancer, the 38 antibodies in Phase 3 studies for non-cancer indications are mostly canonical full-length IgG1, 2 or 4 molecules. Only 4 of the 38 (~11%) are non-canonical molecules: 1 bispecific antibody and 3 antibody ‘fragments’ (scFv, Fab, nanobody). Like ADCs, bispecific antibodies are expected to comprise a larger percentage of the Phase 3 pipeline in the next ~6-8 years. Bispecific antibodies now comprise ~9% of the entire commercial pipeline of antibody therapeutics, but most (32/45, 71%) of those are currently in early clinical studies (either Phase 1 or Phase 1/2). Compared to ADCs, bispecific antibodies are undergoing evaluation in a broader range of indications, although the majority of bispecifics (30/45, 67%) are for cancer and they comprise ~11% of the clinical pipeline of antibodies for cancer. The two bispecific antibodies now on the market, catumaxomab (Removab®) and blinatumomab (BLINCYTO®), are both for cancer. Nevertheless, the one bispecific antibody now in Phase 3 studies, emicizumab, is for a non-cancer indication (hemophilia A).

The clinical pipeline of antibody therapeutics, including at Phase 3, is highly dynamic. The Antibody Society will continue to track antibodies in the clinic, and report progress to its members.

Immunomedics announced the issuance of a novel patent (U.S. Patent 9,375,489) related to the company’s lead cancer therapeutic, sacituzumab govitecan, also known as IMMU-132. This antibody-drug conjugate (ADC) comprises a humanized antibody to the cancer target Trop-2 and is conjugated with SN-38, an active metabolite of the anti-cancer drug irinotecan. The patent entitled “Antibody-SN-38 Immunoconjugates with a CL2A Linker.” is the 28th issued U.S. patent covering the uses and composition of sacituzumab govitecan.

The ADC is in development for the treatment of patients with many diverse solid cancers. The most advanced indication in development is triple-negative breast cancer (TNBC). Phase II are also studies ongoing in patients with metastatic non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC) and in patients with metastatic urothelial cancers. According to Immunomedics’ updated clinical development plan for sacituzumab govitecan, in Q3 of 2016 the company plans to complete enrollment of additional patients into the ongoing single-arm Phase II study for patients with relapsed/refractory metastatic TNBC who received at least 2 prior therapies, including taxane. Immunomedics is collaborating with the FDA for completion of the ongoing Phase II trial and for submitting an Accelerated Approval registration application. Also discussions with the European Medicine Agency (EMA) have been initialized, and EMA has provided the company with advice on the scheduled Phase III trial.

In other news, AbbVie announced safety and preliminary efficacy data from a Phase I study of ABT-414. ABT-414 is an investigational ADC for treatment of epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM). Glioblastoma is the most common and most aggressive type of malignant primary brain tumor and in most cases a fatal disease. Amplified EGFR is the most common genetic mutation associated (~50% are EGFR mutations) with malignant GBM. With standard of care therapy, patients with GBM have a median survival of 15 months after diagnosis and two-year survival is 30%, demonstrating the urgent unmet need for new treatment options.

Published data showed no dose-limiting toxicities and frequent, reversible ocular toxicities. Furthermore, an estimated 30% (n=44) of patients treated with ABT-414 as monotherapy were progression free at six months [95% CI=17, 44] (secondary endpoint). Best Response Assessment in Neuro-Oncology (RANO) Criteria identified two partial responses, 18 patients with stable disease, and 24 with progressive disease for a total of 44 patients with complete data.

First marketing applications were recently submitted for two novel antibody therapeutics, ocrelizumab and inotuzumab ozogamicin, intended as treatments for multiple sclerosis (MS) and CD22-positive acute lymphoblastic leukemia (ALL), respectively. Applications for ocrelizumab (OCREVUS), a humanized IgG1 antibody that targets CD20, as a treatment of relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) are undergoing regulatory review by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). No products are currently approved for both forms of MS. A priority review designation has been granted by FDA, and a first action on ocrelizumab’s biologics license application (BLA) is thus expected by December 28, 2016. The marketing applications are based on positive results from two identical Phase 3 studies (OPERA I and OPERA II) in people with RMS and the Phase 3 ORATORIO study in people with PPMS. All primary and key secondary endpoints were met in these three studies.

The antibody-drug conjugate inotuzumab ozogamicin targets CD22, an antigen found on the surface of cancer cells in most ALL patients. Results of a Phase 3 study evaluating the safety and efficacy of inotuzumab ozogamicin compared with investigator-choice chemotherapy in 326 adult patients with relapsed or refractory CD22-positive ALL were recently published in the New England Journal of Medicine. Improvements over chemotherapy on a number of measures, including complete hematologic remission and progression-free survival, were observed in this study. A marketing application for inotuzumab ozogamicin is undergoing review by the EMA; a BLA submission is likely. Inotuzumab ozogamicin received Breakthrough Therapy designation for ALL from FDA, and priority review of applications is a benefit of the designation, which suggests that an approval by FDA is thus possible by the end of 2016.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review (currently 8 mAbs) in the European Union and United States. The antibody target, format and year of first approval are included. Please log in to access the table, located in the Members Only section.

AbbVie dominated the news in the last weeks of April after announcing the acquisition of Stemcentrx including the company’s late-stage rovalpituzumab tesirine (Rova-T) for $5.8bn. Furthermore, AbbVie partnered up with CytomX to jointly develop and commercialize a probody-drug conjugate (PDC) against CD71.

Stemcentrx’ Rova-T, also known as SC16LD6.5, is addressing small cell lung cancer (SCLC) and other neuroendocrine cancers such as large cell neuroendocrine carcinoma. Rova-T has received orphan drug designation from the FDA for treatment of small cell lung cancer. Rova-T targets delta-like protein 3 (DLL3), which is expressed in >80% SCLC patient tumors and is not present on healthy tissue. Rova-T comprises a D6.5 pyrrolobenzodiazepine (PBD) payload conjugated to cysteine residues on the SC16 antibody, a maleimide-containing linker with an eight-carbon polyethylene glycol spacer, cathepsin B–cleavable valine-alanine dipeptide, and self-immolating group, with an average drug-to-antibody ratio (DAR) of 2. Rova-T represents a multi-billion dollar peak revenue opportunity with expected commercialization in 2018. The acquisition expands AbbVie’s oncology pipeline with four additional early-stage clinical compounds in solid tumor indications and Stemcentrx’ portfolio of preclinical assets.

Together with CytomX, AbbVie will co-develop a PDC against CD71. PDCs contain a masking peptide designed to decreasing target binding to healthy tissue and remain inactive until the molecules are activated proteolytically in the tumor microenvironment, thereby minimizing toxicities. The target, transferrin receptor 1 (TfR1), also known as CD71, is ubiquitously expressed on dividing, normal or healthy cells plus a number of hematologic and solid malignant cancer cells. CD71 mediates transferrin-iron complex uptake, an essential process for cell division and therefore also for tumors. CD71 is homogeneously and highly expressed (3+ expression assessed by IHC) in almost all tumor types, including metastatic tumors. The current PDC approach should avoid targeting the many healthy cell types that also express CD71.

Additionally, Regeneron Pharmaceuticals and MedImmune (wholly owned subsidiary of AstraZeneca) entered into a licensing agreement under which Regeneron will use MedImmune’s PBD-based payload and linker technology to develop ADCs against a number of cancer targets. MedImmune will have the option to develop and commercialize certain products created with this technology in territories outside of the United States.